Sulfur dioxide inhibits vascular smooth muscle cell proliferation via suppressing the Erk/MAP kinase pathway mediated by cAMP/PKA signaling.
The present study was designed to investigate the role of endogenous sulfur dioxide (SO2) in vascular smooth muscle cell (VSMC) proliferation, and explore the possible role of cross-talk between cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) and extracellular signal-regulated kinase (Erk)/mitogen-activated protein kinase (MAPK) pathways in this action. By cell counting, growth curve depict, flow cytometry and bromodeoxyuridine (BrdU) labeling assays, we found that SO2 inhibited VSMC proliferation by preventing cell cycle progression from G1 to S phase and by reducing DNA synthesis. SO2 synthase aspartate aminotransferase (AAT1 and AAT2) overexpression significantly inhibited serum-induced proliferating cell nuclear antigen (PCNA) protein expression in VSMCs, demonstrated by western blot analysis. Moreover, overexpression of AAT1 or AAT2 markedly reduced incorporation of BrdU in serum-treated VSMCs. By contrast, either AAT1 or AAT2 knockdown significantly exacerbated serum-stimulated VSMC proliferation. Thus, both exogenous- and endogenous-derived SO2 suppressed serum-induced VSMC proliferation. However, annexin V-propidium iodide (PI) staining and cell cycle analysis demonstrated that SO2 did not influence VSMC apoptosis in the serum-induced proliferation model. In a platelet-derived growth factor (PDGF)-BB-stimulated VSMC proliferation model, SO2 dephosphorylated the active sites of Erk1/2, MAPK kinase 1/2 and RAF proto-oncogene serine/threonine-protein kinase (c-Raf) induced by PDGF-BB. However, the inactivation of the three kinases of the Erk/MAPK pathway was not due to the separate interferences on them by SO2 simultaneously, but a consequence of the influence on the upstream activity of the c-Raf molecule. Hence, we examined the cAMP/PKA pathway, which could inhibit Erk/MAPK transduction in VSMCs. The results showed that SO2 could stimulate the cAMP/PKA pathway to block c-Raf activation, whereas the Ser259 site on c-Raf had an important role in SO2-induced suppression of Erk/MAPK pathway. The present study firstly demonstrated that SO2 exerted a negative regulation of VSMC proliferation via suppressing the Erk/MAPK pathway mediated by cAMP/PKA signaling.


[Leprosy and medicine II--progress and establishment of an absolute isolation policy].
The leprosy policy of Japan began from when the government enacted "law No. 11 (The leprosy prevention act)" in 1907 (Meiji 40) and several leprosy sanatoriums were built to receive previously homeless patients. Then, with the rise of totalitarianism, the isolation policy of Japan gained national support under the slogan "Patient Relief", which would become a major factor behind the enactment of "Leprosy Prevention Law" in 1931 (Showa 6) by which the leprosy policy was changed to one of absolute isolation aimed at the internment of all leprosy patients. From recent research on the leprosy policy of Japan, the internment of all leprosy patients, isolation for life, social defense, and neglect of patients' human-rights had tragic results in many cases. However, there is little research which can reply clearly to the question of whether the leprosy policy of Japan was really original and what factors led to the formation of the absolute isolation policy. This paper focuses on the relation between leprosy policy and treatment, and from this, I make clear the similarities, or peculiarities, of the isolation policy between Japan and the rest of the world, while clarifying the factors associated with the progress of the absolute isolation policy. The processes involved were historical and medical historical in that the relation between the formation of a national health system and the progress of the isolation policy of Meiji Era, the proposal of the isolation policy by Dr. Keizo Dohi, Dr. Shibasaburo Kitasato, and Dr. Masatsugu Yamane; the practical application of this policy by Dr. Kensuke Mitsuda, and the decision to enact this policy and its support by the Health and Medical Bureau and the Department of the Interior, as well as many other factors, all contributed to the final implementation of the absolute isolation policy.


Evaluation of a multiplex reverse transcription-polymerase chain reaction assay for subtyping hemagglutinin genes 1 and 3 of swine influenza type A virus in clinical samples.
A multiplex reverse transcription-polymerase chain reaction (RT-PCR) assay was developed to detect and identify subtypes of hemagglutinin (H) 1 and H3 swine influenza virus (SIV). Two oligonucleotide primer sets were prepared using published sequence data for H1N1 and H3N2. The PCR products with unique size characteristics of each subtype were sequenced, and the sequences were confirmed to be subtype specific for H gene 1 or 3. These primer sets did not amplify when RT-PCR assay was performed for genomic DNA or RNA from other common swine pathogens. The RT-PCR assay was able to detect viral RNA up to 1 tissue culture infective dose of reference SIV H1N1 or H3N2. The multiplex RT-PCR was applied to 30 SIV isolates subtyped by hemagglutination inhibition (HI) test. Forty-three positive and 20 negative swine field samples for SIV by virus isolation were also tested. Of these 73 SIV-positive samples tested, H1 and H3 were identified in 38 and 28 samples by the multiplex RT-PCR, respectively. The remaining 7 samples were positive for both H1 and H3 genes. No positive reaction was found for all 20 SIV-negative field samples. Subsequently, 235 random field samples from pigs with respiratory problems were tested by the multiplex RT-PCR, and 26 and 13 samples were found to be positive for H1 and H3, respectively. Results of these multiplex RT-PCR were comparable with those of the HI test. These results suggest that multiplex RT-PCR can be a useful test for detection and subtyping of SIV in clinical samples.


Igf2 imprinting in development and disease.
Igf2 is one of the first imprinted genes discovered and occupies a centre stage in the study of imprinting. This is because it has dramatic effects on the control of fetal growth, it is involved in growth disorders and in cancer, it interacts with products of other imprinted genes, and its imprinting status is under complex regulation in a cluster of tightly linked imprinted genes. Here we review briefly the key features of Igf2 imprinting in normal development and in disease, and hope to show what a fascinating subject of study this gene and its biology provides.


Combined Exposure of Activated Intestinal Epithelial Cells to Nondigestible Oligosaccharides and CpG-ODN Suppresses Th2-Associated CCL22 Release While Enhancing Galectin-9, TGFβ, and Th1 Polarization.
Short-chain galacto- and long-chain fructo-oligosaccharides (scGOS/lcFOS) and CpG-ODN affect intestinal epithelial cells (IEC). Epithelial IL1α may contribute to allergic sensitization via autocrine mediator release affecting dendritic cells (DC). We studied whether IL1α contributes to Th2-associated mediator release by activated IEC and IEC/DC cocultures and possible modulation by scGOS/lcFOS±CpG-ODN. Solid phase or transwell cultured IEC were preincubated with IL1α and/or IFNγ/TNFα for 6 h. The transwell IEC were also apically exposed to scGOS/lcFOS±CpG-ODN for 6 h, washed, and re-exposed, while cocultured with immature moDC (ccDC) for 48 h. These ccDC were subsequently added to allogeneic naïve T cells (MLR). IEC- and/or DC-derived mediators and T cell cytokines were measured. IL1α tended to enhance IL25 and enhanced IL33 and CCL20 release by IEC, while IL1α or TNFα or IFNγ enhanced CCL22. These were all further increased upon combined exposure of IFNγ/TNFα±IL1α coinciding with increased IL33 secretion in the solid phase culture. In the transwell, IL25 and IL33 remained under detection, while CCL20 and CCL22 were induced by IL1α or IFNγ/TNFα, respectively, and a synergistic increase was observed upon combined exposure of IFNγ/TNFα and IL1α. Furthermore, IFNγ was found to enhance galectin-9 secretion, which was more pronounced in IFNγ/TNFα±IL1α-exposed IEC and coincided with TGFβ increase. Epithelial CpG-ODN exposure further increased CCL20, while reducing CCL22 release by IFNγ/TNFα/IL1α-activated IEC; however, scGOS/lcFOS suppressed both. Combined scGOS/lcFOS and CpG-ODN reduced CCL22, while CCL20 and regulatory galectin-9 and TGFβ remained high in the supernatant of IFNγ/TNFα/IL1α-activated IEC and the following IEC/DC coculture. ccDC of scGOS/lcFOS- and CpG-ODN-exposed IFNγ/TNFα/IL1α-activated IEC increased IFNγ, IL10, TGFβ, and galectin-9 secretion in the MLR compared to ccDC exposed to control-activated IEC. IL1α enhanced CCL20 and Th2-associated CCL22 release by IFNγ/TNFα-activated IEC. Combined scGOS/lcFOS and CpG-ODN exposure suppressed CCL22, while maintaining high CCL20, TGFβ, and galectin-9 concentrations. In addition, ccDC derived from this IEC/DC coculture enhanced Th1 and regulatory mediator secretion mimicking known in vivo effects.


Total Synthesis of (-)-Lasonolide A.
The lasonolides are novel polyketides that have displayed remarkable biological activity in vitro against a variety of cancer cell lines. Herein we describe our first-generation approach to the formal synthesis of lasonolide A. The key findings from these studies ultimately allowed us to go on and complete a total synthesis of lasonolide A. The convergent approach unites two highly complex fragments utilizing a Ru-catalyzed alkene-alkyne coupling. This type of coupling typically generates branched products; however, through a detailed investigation, we are now able to demonstrate that subtle structural changes to the substrates can alter the selectivity to favor the formation of the linear product. The synthesis of the fragments features a number of atom-economical transformations which are highlighted by the discovery of an engineered enzyme to perform a dynamic kinetic reduction of a β-ketoester to establish the absolute stereochemistry of the southern tetrahydropyran ring with high levels of enantioselectivity.


Rapid Systematic Review: The Appropriate Use of Quick Sequential Organ Failure Assessment (qSOFA) in the Emergency Department.
The concept of sepsis has recently been redefined by an International Task Force. The task force recommended the use of the quick Sequential Organ Failure Assessment (qSOFA) score instead of Systemic Inflammatory Response Syndrome (SIRS) criteria to identify patients at high risk of mortality from sepsis outside of the intensive care unit, including in emergency departments (EDs). However, the primary outcome for qSOFA is prediction of risk for mortality, which is not the principal outcome measure considered in the ED. From the ED perspective, the priorities are the identification (diagnosis) of the septic patient and then the initiation of time-sensitive, life-saving interventions. We performed a structured review of PubMed from January 2012 to December 2018, limited to reports involving human subjects and written in English language and containing relevant keywords. The highest-quality studies were then reviewed in a structured format. We utilized these studies to estimate the sensitivity and specificity of SIRS and qSOFA for diagnosis of sepsis. Thirteen unique articles were identified for further review, and the 11 highest-grade articles (C and D) were determined to be appropriate for inclusion in this review, and the two low-grade articles were excluded (E). Based on multiple retrospective and few prospective studies, it appears that qSOFA performs poorly in comparison with SIRS as a diagnostic tool for ED patients who may have sepsis or septic shock. However, qSOFA does have a strong prognostic accuracy for mortality in those ED patients already diagnosed with sepsis or septic shock.


Continuing Bonds in the Existential, Phenomenological, and Cultural Study of Grief: Prolegomena.
The essay makes the case that continuing bonds is a useful perspective for bereavement studies based in existential, phenomenological, and cultural philosophy. First, the idea of continuing bonds has explanatory power for many phenomena in individual and family grief and in the multiple interactions between individual/family grief and larger social/cultural dynamics. Second, in the study of continuing bonds we find concepts that are akin to those in phenomenology and existentialism. Using some of my own scholarship and the scholarship of many others, the essay is structured by themes Edith Marie Steffen and I found in our 2018 anthology on developments in the continuing bonds model in the two decades after it was introduced: Continuing bonds (1) are inter-subjective, (2) are central in constructing meaning, (3) raise questions about the ontological status of our interactions with the dead, and (4) are best understood within their cultural setting.


Level of Activity in Profound/Severe Mental Retardation (LAPMER): a Rasch-derived scale of disability.
Classification of Mental Retardation (MR) into severe and profound is based on IQ threshold (<35 and 20% respectively) and on quite generic descriptions of deficits in adaptive behavior. The LAPMER scale (after Level of Activity in Profound/severe Mental Retardation) was developed as a measure of severity through observed behavior in adult patients. The Rasch analysis (RA, in its rating scale model) was adopted as a guide for selection of items, conceptualization of item levels, and validation of the overall instrument. The RA provides estimates on a continuum measure corresponding to the discrete cumulative score. A model prescribes the expected scores on each subject-item interaction. Discrepancies between observed and expected scores allow diagnostic procedures on coherence (fit) of both subjects and items. The final version included 8 items: Feeding, Sphincters, Communication, Manipulation, Dressing, Locomotion, Spatial Orientation and Praxiae, scored 0/1 or 0/1/2 (cumulative range for the total set of items was 0-13) the higher the score, the better the performance. The test can be administered in 15 minutes through observation or inquiry from proxies and personnel. A psychologist rated 146 permanent hosts of a large Institute for mentally retarded adults (51 profound and 95 severe, 91 male, age 18-63, median 36). Median score was 6/13, IQR 1-9, range 0-12, 19% of cases scored 0. Cronbach a for internal consistency was 0.90. Fifty-seven patients were also independently scored by another psychologist. Between-rater Cohen's k reliability index ranged from 0.77-0.96 across items. Median raw scores were 1 and 8 in profound and severe cases, respectively (p<0.001). Rasch person reliability coefficient, a 0 to 1 index of internal consistency analogous to Crohnbach a, was 0.92. For each item the standardized differences between observed and model-expected scores (residuals) were c2 tested (a level 0.05) across sub-groups of patients. These were: profound vs. severe cases, and classes of motor impairment (tetra-,hemi-,para-plegic and unimpaired), matched for overall ability measure. For 6 items some residuals were found to be statistically significant. Absolute differences ranged from 0 to 0.7 raw score points, with no systematic patterns. Gender, age group and rater did not bias the measure. Residuals did not correlate meaningfully across pairs of items (r<(0.5)), further supporting the unidimensionality of the measure. The scale seems a valid tool for classification of adult severe and profound MR cases.


Dominance of IMP-4-producing enterobacter cloacae among carbapenemase-producing Enterobacteriaceae in Australia.
The prevalence of carbapenemase-producing Enterobacteriaceae (CPE) has been increasing worldwide. blaIMP has been reported to be the predominant carbapenemase-encoding gene within Enterobacteriaceae in Australia. However, there are limited data currently available on CPE from Queensland, Australia. A total of 58 CPE isolates were isolated between July 2009 and March 2014 from Queensland hospitals. The clonality of isolates was determined by Diversilab repetitive sequence-based PCR. The isolates were investigated for the resistance mechanisms carbapenemase, extended-spectrum β-lactamase, and AmpC β-lactamase and for aminoglycoside resistance and plasmid-mediated quinolone resistance genes by PCR. The plasmid types associated with carbapenemase-encoding genes were characterized. The majority of the CPE were Enterobacter cloacae (n = 29). The majority of Queensland CPE isolates were IMP producers and comprised 11 species (n = 48). Nine NDM-producing Enterobacteriaceae were identified. One NDM-producing Klebsiella pneumoniae isolate coproduced OXA-48. One K. pneumoniae isolate was an OXA-181 producer. The incidence of IMP producers increased significantly in 2013. blaIMP-4 was found in all IMP-producing isolates. blaTEM, qnrB, and aacA4 were common among IMP-4 producers. The HI2 (67%) and L/M (21%) replicons were associated with blaIMP-4. All HI2 plasmids were of sequence type 1 (ST1). All but one of the NDM producers possessed blaCTX-M-15. The 16S rRNA methylase genes found among NDM producers were armA, rmtB, rmtC, and rmtF. The substantial increase in the prevalence of CPE in Queensland has been associated mainly with the emergence E. cloacae strains possessing HI2 plasmids carrying blaIMP-4 over the past 2 years. The importation of NDM producers and/or OXA-48-like producers in patients also contributed to the increased emergence of CPE.


The F-BAR protein CIP4 promotes GLUT4 endocytosis through bidirectional interactions with N-WASp and Dynamin-2.
F-BAR proteins are a newly described family of proteins with unknown physiological significance. Because F-BAR proteins, including Cdc42 interacting protein-4 (CIP4), drive membrane deformation and affect endocytosis, we investigated the role of CIP4 in GLUT4 traffic by flow cytometry in GLUT4myc-expressing L6 myoblasts (L6 GLUT4myc). L6 GLUT4myc cells express CIP4a as the predominant F-BAR protein. siRNA knockdown of CIP4 increased insulin-stimulated (14)C-deoxyglucose uptake by elevating cell-surface GLUT4. Enhanced surface GLUT4 was due to decreased endocytosis, which correlated with lower transferrin internalization. Immunoprecipitation of endogenous CIP4 revealed that CIP4 interacted with N-WASp and Dynamin-2 in an insulin-dependent manner. FRET confirmed the insulin-dependent, subcellular properties of these interactions. Insulin exposure stimulated specific interactions in plasma membrane and cytosolic compartments, followed by a steady-state response that underlies the coordination of proteins needed for GLUT4 traffic. Our findings reveal a physiological function for F-BAR proteins, supporting a previously unrecognized role for the F-BAR protein CIP4 in GLUT4 endocytosis, and show that interactions between CIP4 and Dynamin-2 and between CIP4 and NWASp are spatially coordinated to promote function.


Self-Differentiation, Psychological Flexibility, and Difficulties in Practice in Social Workers and Social Work Students.
Practicing social work involves unique difficulties, which may vary with seniority. This study aimed to identify these difficulties among social workers and social work students and to examine the associations between psychological flexibility (PF), self-differentiation (SF), and difficulties in practice in both groups. Ninety-one social work students and seventy-five social workers completed the following questionnaires: Difficulties in Practice, the Acceptance and Action Questionnaire-II, and Differentiation of Self Inventory. Results showed higher difficulties among social work students regarding their professional competence. Social workers demonstrated higher levels of PF, while no significant difference was found in SF. SF and PF were positively correlated, and both were negatively correlated with difficulties in practice in both groups. Among social work students, a moderating effect of PF was found for the association between SF and difficulties in practice. The current study emphasizes the importance of developing SF and cultivating PF during social work education to enhance professional competence and reduce difficulties in practice.


Narrow Band Active Contour Attention Model for Medical Segmentation.
Medical image segmentation is one of the most challenging tasks in medical image analysis and widely developed for many clinical applications. While deep learning-based approaches have achieved impressive performance in semantic segmentation, they are limited to pixel-wise settings with imbalanced-class data problems and weak boundary object segmentation in medical images. In this paper, we tackle those limitations by developing a new two-branch deep network architecture which takes both higher level features and lower level features into account. The first branch extracts higher level feature as region information by a common encoder-decoder network structure such as Unet and FCN, whereas the second branch focuses on lower level features as support information around the boundary and processes in parallel to the first branch. Our key contribution is the second branch named Narrow Band Active Contour (NB-AC) attention model which treats the object contour as a hyperplane and all data inside a narrow band as support information that influences the position and orientation of the hyperplane. Our proposed NB-AC attention model incorporates the contour length with the region energy involving a fixed-width band around the curve or surface. The proposed network loss contains two fitting terms: (i) a high level feature (i.e., region) fitting term from the first branch; (ii) a lower level feature (i.e., contour) fitting term from the second branch including the (ii1) length of the object contour and (ii2) regional energy functional formed by the homogeneity criterion of both the inner band and outer band neighboring the evolving curve or surface. The proposed NB-AC loss can be incorporated into both 2D and 3D deep network architectures. The proposed network has been evaluated on different challenging medical image datasets, including DRIVE, iSeg17, MRBrainS18 and Brats18. The experimental results have shown that the proposed NB-AC loss outperforms other mainstream loss functions: Cross Entropy, Dice, Focal on two common segmentation frameworks Unet and FCN. Our 3D network which is built upon the proposed NB-AC loss and 3DUnet framework achieved state-of-the-art results on multiple volumetric datasets.


[The action of sodium oxybutyrate and emoxypin on the functional state of the adrenaline-damaged myocardium in an experiment].
The effect of agents possessing antihypoxic and antioxidant activity, namely sodium oxybutyrate and emoxypin, on the functional state of the heart muscle was studied in experiments on dogs with epinephrine necroses of the myocardium. A marked cardioprotective effect was produced by sodium oxybutyrate infused intravenously (200 mg/kg) either 10 min or 2 hrs after myocardial damage had been modelled and by emoxypin (4 mg/kg; 0.4 mg/kg) infused intravenously 30 min after the damage.


Health care costs during the last 12 months of life in Israel: estimation and implications for risk-adjustment.
Accumulating research shows that decedents' costs are high, they increase towards death, and they comprise a large proportion of total lifetime costs. The objectives of this paper are (i) to examine the Israeli pattern of medical care cost during the 12 months prior to death by gender, age, and chronic conditions, and (ii) to examine the implications of the results for the Israeli risk adjustment scheme. For the first objective, we used 12 month follow-up data on a cohort of decedents. For the second objective, we supplemented the data with a cross-section of enrollees (survivors and decedents in 2004). With regard to the first objective, we found that the broad Israeli patterns of cost match previous studies from other countries. With respect to the second objective, we argue that since the cost during the last 12 months of life is very high and is concentrated among relatively few persons, in order to prevent any adverse incentives caused by the combination of age-based risk adjustment and segmentation of end-of-life health care, death should be introduced into the existing retrospective risk-sharing arrangement.


Prenatal stress causes dendritic atrophy of pyramidal neurons in hippocampal CA3 region by glutamate in offspring rats.
A substantial number of human epidemiological data, as well as experimental studies, suggest that adverse maternal stress during gestation is involved in abnormal behavior, mental, and cognition disorder in offspring. To explore the effect of prenatal stress (PS) on hippocampal neurons, in this study, we observed the dendritic field of pyramidal neurons in hippocampal CA3, examined the concentration of glutamate (Glu), and detected the expression of synaptotagmin-1 (Syt-1) and N-methyl-D-aspartate receptor 1 (NR1) in hippocampus of juvenile female offspring rats. Pregnant rats were divided into two groups: control group (CON) and PS group. Female offspring rats used were 30-day old. The total length of the apical dendrites of pyramidal neurons in hippocampal CA3 of offspring was significantly shorter in PS than that in CON (p < 0.01). The number of branch points of the apical dendrites of pyramidal neurons in hippocampal CA3 of offspring was significantly less in PS (p < 0.01). PS offspring had a higher concentration of hippocampal Glu compared with CON (p < 0.05). PS offspring displayed increased expression of Syt-1 and decreased NR1 in hippocampus compared with CON (p < 0.001 and p < 0.01, respectively). The expression of NR1 in different hippocampus subfields of offspring was significantly decreased in PS than that in CON (p < 0.05-0.01). This study shows that PS increases the Glu in hippocampus and causes apical dendritic atrophy of pyramidal neurons of hippocampal CA3 in offspring rats. The decline of NR1 in hippocampus may be an adaptive response to the increased Glu.


Minimizing sample error in transmission electron microscopy.
The last few years have seen an increase in the use of electron microscopy, both for research and as a diagnostic tool in pathology. With the increase in the number of specimens being used for diagnostic purposes, limitations due to sampling error have become apparent. The method described is designed to help overcome this problem.


Tracing the evolution of a large protein complex in the eukaryotes, NADH:ubiquinone oxidoreductase (Complex I).
The increasing availability of sequenced genomes enables the reconstruction of the evolutionary history of large protein complexes. Here, we trace the evolution of NADH:ubiquinone oxidoreductase (Complex I), which has increased in size, by so-called supernumary subunits, from 14 subunits in the bacteria to 30 in the plants and algae, 37 in the fungi and 46 in the mammals. Using a combination of pair-wise and profile-based sequence comparisons at the levels of proteins and the DNA of the sequenced eukaryotic genomes, combined with phylogenetic analyses to establish orthology relationships, we were able to (1) trace the origin of six of the supernumerary subunits to the alpha-proteobacterial ancestor of the mitochondria, (2) detect previously unidentified homology relations between subunits from fungi and mammals, (3) detect previously unidentified subunits in the genomes of several species and (4) document several cases of gene duplications among supernumerary subunits in the eukaryotes. One of these, a duplication of N7BM (B17.2), is particularly interesting as it has been lost from genomes that have also lost Complex I proteins, making it a candidate for a Complex I interacting protein. A parsimonious reconstruction of eukaryotic Complex I evolution shows an initial increase in size that predates the separation of plants, fungi and metazoa, followed by a gradual adding and incidental losses of subunits in the various evolutionary lineages. This evolutionary scenario is in contrast to that for Complex I in the prokaryotes, for which the combination of several separate, and previously independently functioning modules into a single complex has been proposed.


A simple surgical method of treating pilonidal sinus.
A simple surgical method of treatment was used in 63 patients with pilonidal sinus. Adequate block excision with primary closure is the basis of this technique. The problem of closure and obliteration of the dead space was solved by using absorbable sutures to unite fascia and subcutis in the midline, after mobilization of the skin and subcutaneous layers of the wound edges. In 59 (93.6%) of 63 patients treated, primary healing was obtained; in 4 (6.4%) disturbances of wound healing occured; and in 3 (4..8%) recurrences developed. The average stay in hospital was 10.4 days and the average healing time 10 days. The follow-up period was between 1 year and 6 years. The scars were sound, supple and painless. Our results include 6 patients, treated several days before the definitive procedure by incision and drainage for a pilonidal abscess. Antibiotic or chemotherapeutic agents were not used.


Synergistic effect of quorum sensing genes in biofilm development and PAHs degradation by a marine bacterium.
Quorum sensing (QS) is a prevalently found intercellular signaling system in bacteria. QS system bestows behavioral coordination ability in bacteria at high population density. QS via acylated homoserine lactone (AHL) is extensively conserved in Gram-negative bacteria and plays crucial role in regulating many biological processes. The role of QS genes coding for AHL synthase enzyme (lasI and rhlI) was established in bioremediation of polycyclic aromatic hydrocarbons (PAHs) viz. phenanthrene and pyrene. AHL producing biofilm forming marine bacterium Pseudomonas aeruginosa N6P6 was isolated by selective enrichment on PAHs. AHL production was confirmed using AHL bioreporters and GC-MS analysis. Biofilm development and its architecture was significantly (P < 0.05) affected by alterations in lasI/rhlI expression. The lasI/rhlI gene expression pattern significantly influences biofilm formation and subsequent degradation of PAHs. The integrated density of Pseudomonas aeruginosa N6P6 biofilm was highest for 48 h old biofilm and the PAHs (phenanthrene and pyrene) degradation was also found maximum (85.6 % and 47.56 %) with this biofilm. A significant positive correlation (P < 0.05) was observed between lasI expression and PAHs degradation. The role of QS genes in biofilm formation and degradation of PAHs was validated by blocking the transcription of lasI/rhlI by a QS inhibitor (QSI) tannic acid. Further, application of such QS positive isolates in PAHs contaminated sites could be a promising strategy to improve the PAHs bioremediation.


Pathogenesis and pathology of shoulder ulcerations in sows with special reference to peripheral nerves and behavioural responses to palpation.
Shoulder ulcerations are common in breeding sows in production systems but the consequences for the animals in terms of pain or discomfort are not well-described. This study presents data from a histopathological examination of shoulders of sows, specially focusing on the peripheral nerves in the region and the behavioural responses towards palpation of animals with traumatic neuromas but without ulcers. The study included 155 sows from seven Danish herds initially screened and stratified according to absence/presence and size of shoulder ulcers 3-4 weeks post-partum, out of which 71 were free of ulcerations and 84 had different stages of ulceration. Before collection, sows were subjected to shoulder palpation and behavioural responses were registered. From the consecutive pattern of development of ulcerations it is evident that shoulder ulcerations develop from top-to-bottom. A high frequency of traumatic neuromas was found in both healed and unhealed lesions. The observation of viable nerve-ends in shoulder ulcerations makes it likely that ulcerations are associated with pain. Moreover, the presence of traumatic neuromas in healed ulcerations indicates that there is discomfort even after the lesions have healed. This is further supported by the behavioural finding that rubbing behaviour in response to palpation was increased on the day of sample collection of the shoulders in sows with traumatic neuromas but without shoulder ulcers (P=0.053). Further studies are needed for final confirmation but these results suggest that shoulder ulcers may be associated with pain even after healing.


[Successful surgical repair of aortic arch torsion and aneurysm].
Described herein is a rarely encountered in clinical practice case regarding surgical management of pathological tortuosity of the aortic arch with a simultaneously present aneurysm thereof. The defect was surgically corrected in the setting of extracorporeal circulation. The tortuous and aneurysmatic aortic arch was resected within the boundaries of the healthy tissues, duly followed by establishing an end-to-end anastomosis between the edges of the resected aorta.


Charge Density Gradient Propelled Ultrafast Sweeping Removal of Dropwise Condensates.
Continuous sweeping of dropwise condensates is an effective form of vapor to liquid transition in terms of thermal transport at a solid/liquid interface. However, using conventional approaches, it is difficult to simultaneously achieve small activating size and fast departure of condensed droplets with high efficiency, due to the insufficient driving force compared to adhesion. Here, we propose an unexplored method to stimulate a frequent sweeping removal of dropwise condensates at ultrahigh efficiency on a superhydrophobic substrate, aided by a charge density gradient (CDG). We show that the CDG can be injected inside a superhydrophobic substrate on which the condensate droplet with jump-induced charges starts to sweep at a small size down to the microscale followed by quick snowball-like growing and chase-like propelling. The incorporation of the CDG on a superhydrophobic substrate enables a continuous, fast, frequent, long-range, and gravity-independent droplet removal during condensation, making this strategy a promising solution for diverse applications in water harvesting, antifogging, and anti-icing.


Rapid tilt-series acquisition for electron cryotomography.
Using a new Titan Krios stage equipped with a single-axis holder, we developed two methods to accelerate the collection of tilt-series. We demonstrate a continuous-tilting method that can record a tilt-series in seconds, but with loss of details finer than ∼4 nm. We also demonstrate a fast-incremental method that can record a tilt-series several-fold faster than current methods and with similar resolution. We characterize the utility of both methods in real biological electron cryotomography workflows. We identify opportunities for further improvements in hardware and software and speculate on the impact such advances could have on structural biology.


Randomized controlled trial of botulinum toxin versus laparoscopic heller myotomy for esophageal achalasia.
To compare laparoscopic cardia myotomy and fundoplication with botulinum toxin (BoTx) injection in patients with esophageal achalasia. Although myotomy is thought to offer better results, recent studies have reported 80% success rates after 2 BoTx injections a month apart. No randomized controlled trials comparing the 2 treatments have been published so far. Newly diagnosed achalasia patients were randomly assigned to BoTx injection or laparoscopic myotomy. Symptoms were scored; lower esophageal sphincter resting and nadir pressures were measured by manometry; barium swallow was used to assess esophageal diameter pre- and post-treatment. Eight to one hundred units of BoTx were injected twice, a month apart, at the esophagogastric junction. Myotomy included anterior partial (Dor) or Nissen fundoplication. Eighty patients were involved in the study: 40 received BoTx and 40 underwent myotomy. Mortality was nil. One surgical patient bled from the trocar site. Median hospital stay was 6 days for surgery; BoTox patients were treated as day-hospital admissions. All patients completed the follow-up. After 6 months, the results in the 2 groups were comparable, although symptom scores improved more in surgical patients (82% confidence interval [CI] 76-89 vs. 66% CI 57-75, P < 0.05). The drop in lower esophageal sphincter pressure was similar in the 2 groups; the reduction in esophageal diameter was greater after surgery (19% CI 13-26 vs. 5% CI 2-11, P < 0.05). Later on, symptoms recurred in 65% of the BoTx-treated patients and the probability of being symptom-free at 2 years was 87.5% after surgery and 34% after BoTx (P < 0.05). Laparoscopic myotomy is as safe as BoTx treatment and is a 1-shot treatment that cures achalasia in most patients. BoTx should be reserved for patients who are unfit for surgery or as a bridge to more effective therapies, such as surgery or endoscopic dilation.


Prospective Evaluation of Health Literacy and Its Impact on Outcomes in Emergency General Surgery.
Health literacy (HL) is an important component of national health policy. The aim of our study was to assess the prevalence of low HL (LHL) and determine its impact on outcomes after emergency general surgery (EGS). We performed a (2016-2017) prospective cohort analysis of adult EGS patients. HL was assessed using the Short Assessment of HL score. LHL was defined as Short Assessment of HL score <14. Outcomes were the prevalence of LHL, compliance with medications, wound/drain care, 30-d complications, 30-d readmission, and time to resuming activities of daily living. We enrolled 900 patients. The mean age was 43 ± 11 y. Overall, 22% of the patients had LHL. LHL patients were more likely to be Hispanics (59% versus 15%, P < 0.01), uninsured (50% versus 20%, P < 0.01), have lower socioeconomic status (80% versus 40%, P < 0.02), and are less likely to have completed college (5% versus 60%, P < 0.01) compared with HL patients. On regression analysis, LHL was associated with lower medication compliance (OR: 0.81, [0.4-0.9], P = 0.02), inadequate wound/drain care (OR: 0.75, [0.5-0.8], P = 0.01), 30-d complications (OR: 1.95, [1.3-2.5], P < 0.01), and 30-d readmission (OR: 1.51, [1.2-2.6], P = 0.02). The median time of resuming activities of daily living was longer in patients with LHL than HL patients (4 d versus 7 d, P < 0.01). One in five patients undergoing EGS has LHL. LHL is associated with decreased compliance with discharge instructions, medications, and wound/drain care. Health literacy must be taken into account when discussing the postoperative plan and better instruction is needed for patients with LHL. Level III. Prognostic.


In vitro synergistic effect of Hibiscus sabdariffa aqueous extract in combination with standard antibiotics against Helicobacter pylori clinical isolates.
Context The increasing problem of drug-resistant strains has led to the failure of current treatment regimens of Helicobacter pylori (HP) infection. Recently, a new treatment strategy has been developed to overcome the problem by using natural products in combination with antibiotics to enhance the treatment efficacy. Objective The antimicrobial combinatory effect of the aqueous extract of Hibiscus sabdariffa L. (Malvaceae) (AEHS) with antibiotics (clarithromycin, CLA; amoxicillin, AMX; metronidazole, MTZ) has been evaluated in vitro against HP strains. Materials and methods Hibiscus calyces (35 g) were brewed in 250 mL of boiled water for 30 min, and minimum inhibitory concentrations (MICs) were determined by agar dilution method. The checkerboard assay was used to evaluate the antimicrobial combinatory effect according to the sum of fractional inhibitory concentration (∑FIC) indices. Results In this study, AEHS exerted remarkable bacteriostatic effect against all HP strains tested with MICs values ranging from 9.18 to 16.68 μg/mL. Synergy effect of AEHS with CLA or MTZ was obtained against four of seven HP strains tested with ∑FIC ranging from 0.21 to 0.39. The additive effect of AEHS with AMX was obtained against five of seven HP strains tested with ∑FIC ranging from 0.61 to 0.91. Conclusion This study presents AEHS as a potent therapeutic candidate alone, or in combination with antibiotics for the treatment of HP infection.


Isolating SARS-CoV-2 Strains From Countries in the Same Meridian: Genome Evolutionary Analysis.
COVID-19, caused by the novel SARS-CoV-2, is considered the most threatening respiratory infection in the world, with over 40 million people infected and over 0.934 million related deaths reported worldwide. It is speculated that epidemiological and clinical features of COVID-19 may differ across countries or continents. Genomic comparison of 48,635 SARS-CoV-2 genomes has shown that the average number of mutations per sample was 7.23, and most SARS-CoV-2 strains belong to one of 3 clades characterized by geographic and genomic specificity: Europe, Asia, and North America. The aim of this study was to compare the genomes of SARS-CoV-2 strains isolated from Italy, Sweden, and Congo, that is, 3 different countries in the same meridian (longitude) but with different climate conditions, and from Brazil (as an outgroup country), to analyze similarities or differences in patterns of possible evolutionary pressure signatures in their genomes. We obtained data from the Global Initiative on Sharing All Influenza Data repository by sampling all genomes available on that date. Using HyPhy, we achieved the recombination analysis by genetic algorithm recombination detection method, trimming, removal of the stop codons, and phylogenetic tree and mixed effects model of evolution analyses. We also performed secondary structure prediction analysis for both sequences (mutated and wild-type) and "disorder" and "transmembrane" analyses of the protein. We analyzed both protein structures with an ab initio approach to predict their ontologies and 3D structures. Evolutionary analysis revealed that codon 9628 is under episodic selective pressure for all SARS-CoV-2 strains isolated from the 4 countries, suggesting it is a key site for virus evolution. Codon 9628 encodes the P0DTD3 (Y14_SARS2) uncharacterized protein 14. Further investigation showed that the codon mutation was responsible for helical modification in the secondary structure. The codon was positioned in the more ordered region of the gene (41-59) and near to the area acting as the transmembrane (54-67), suggesting its involvement in the attachment phase of the virus. The predicted protein structures of both wild-type and mutated P0DTD3 confirmed the importance of the codon to define the protein structure. Moreover, ontological analysis of the protein emphasized that the mutation enhances the binding probability. Our results suggest that RNA secondary structure may be affected and, consequently, the protein product changes T (threonine) to G (glycine) in position 50 of the protein. This position is located close to the predicted transmembrane region. Mutation analysis revealed that the change from G (glycine) to D (aspartic acid) may confer a new function to the protein-binding activity, which in turn may be responsible for attaching the virus to human eukaryotic cells. These findings can help design in vitro experiments and possibly facilitate a vaccine design and successful antiviral strategies.


Overexpression of the human vitamin D3 receptor in mammalian cells using recombinant adenovirus vectors.
The human vitamin D3 receptor (hVDR) cDNA was cloned into the E1 region of the adenovirus genome to generate recombinant viruses which were used to infect 293 (adenovirus-transformed human fetal kidney) cells. High salt extracts from cells infected with the recombinant viruses were subjected to immunoblot analysis using a monoclonal antibody to chicken VDR and were shown to contain large quantities of a protein of approximately 50 kDa with a migration identical to that of the hVDR in T47D (human mammary adenocarcinoma) cells. Scatchard analysis showed that the infected cells express approximately 100-fold more receptor than T47D cells and that this receptor binds 1,25-dihydroxyvitamin D3 with high affinity. The overexpressed hVDR also binds to DNA-cellulose and is eluted with a KCl concentration similar to that determined for fully active endogenous VDR. Nuclear extracts from cells infected with the hVDR-expressing adenoviruses contain an activity that specifically binds an oligonucleotide with sequences from the rat osteocalcin vitamin D3 response element, as determined by gel mobility shift. This interaction can be inhibited by the presence of an anti-VDR antibody, but not by nonspecific immunoglobulins. We conclude, therefore, that the overexpressed receptor has the ligand- and DNA-binding characteristics defined for endogenous VDR and that adenoviruses can be used to efficiently express large quantities of functional hVDR in a human cell line. Finally, a second binding activity, specific for the vitamin D response element, but distinct from the VDR, has been identified in extracts from uninfected cells.


The timescale of phenotypic plasticity and its impact on competition in fluctuating environments.
Although phenotypic plasticity can be advantageous in fluctuating environments, it may come too late if the environment changes fast. Complementary chromatic adaptation is a colorful form of phenotypic plasticity, where cyanobacteria tune their pigmentation to the prevailing light spectrum. Here, we study the timescale of chromatic adaptation and its impact on competition among phytoplankton species exposed to fluctuating light colors. We parameterized a resource competition model using monoculture experiments with green and red picocyanobacteria and the cyanobacterium Pseudanabaena, which can change its color within approximately 7 days by chromatic adaptation. The model predictions were tested in competition experiments, where the incident light color switched between red and green at different frequencies (slow, intermediate, and fast). Pseudanabaena (the flexible phenotype) competitively excluded the green and red picocyanobacteria in all competition experiments. Strikingly, the rate of competitive exclusion was much faster when the flexible phenotype had sufficient time to fully adjust its pigmentation. Thus, the flexible phenotype benefited from its phenotypic plasticity if fluctuations in light color were relatively slow, corresponding to slow mixing processes or infrequent storms in their natural habitat. This shows that the timescale of phenotypic plasticity plays a key role during species interactions in fluctuating environments.


Early postnatal growth of Basotho infants in the Mantsonyane area, Lesotho.
The records of 814 infants born in a rural hospital in Lesotho were analysed. It was calculated that on average Basotho infants regained their birthweight between 3 and 4 days of age and the average weight loss amounted to 3%. Compared with Caucasian infants, Basotho infants regained their birthweight sooner. Of 289 infants in whom the gestational age was assessed, small-for-dates infants showed an increased mean growth rate compared with pre-term and appropriate-for-dates full-term infants.


HBOC-201 as an alternative to blood transfusion: efficacy and safety evaluation in a multicenter phase III trial in elective orthopedic surgery.
The ability of hemoglobin based oxygen carrier-201 (HBOC-201) to safely reduce and/or eliminate perioperative transfusion was studied in orthopedic surgery patients. A randomized, single-blind, packed red blood cell (PRBC)-controlled, parallel-group multicenter study was conducted. Six hundred eighty-eight patients were randomized to treatment with HBOC-201 (H, n = 350) or PRBC (R, n = 338) at the first transfusion decision. Primary endpoints were transfusion avoidance and blinded assessment [Mann-Whitney estimator (MW)] of safety noninferiority. Groups were compared directly and by paired/matching group analyses predicated on a prospectively defined dichotomy [treatment success (HH) vs. failure (HR)] in the H arm and an equivalently defined dichotomy [</=3 (R3-) vs. >3 (R3+) units PRBC] in the R arm, based on need (moderate vs. high) for additional oxygen carrying capacity. A total of 59.4% of patients in the H arm avoided PRBC transfusion. Adverse events (8.47 vs. 5.88), and serious adverse events (SAEs) (0.35 vs. 0.25) per patient were higher in the H versus R arms (p < 0.001 and p < 0.01) with MW = 0.561 (95 CI 0.528-0.594). HH versus R3- had identical (0.14) serious adverse events/patient and a MW = 0.519 (95% confidence limit 0.481-0.558), whereas the incidence was higher (0.63 vs. 0.47) for HR versus R3+ with a MW = 0.605 (95% confidence limit 0.550-0.662). Age (>80 years), volume overload and undertreatment contributed to this imbalance. HBOC-201 eliminated transfusion in the majority of subjects. The between arms (H vs. R) safety analysis was unfavorable and likely related to patient age, volume overload, and undertreatment and was isolated to patients that could not be managed by HBOC-201 alone. However, patients <80 years old with moderate clinical need may safely avoid transfusion when treated with up to 10 units of HBOC-201.


Multi-target-qubit unconventional geometric phase gate in a multi-cavity system.
Cavity-based large scale quantum information processing (QIP) may involve multiple cavities and require performing various quantum logic operations on qubits distributed in different cavities. Geometric-phase-based quantum computing has drawn much attention recently, which offers advantages against inaccuracies and local fluctuations. In addition, multiqubit gates are particularly appealing and play important roles in QIP. We here present a simple and efficient scheme for realizing a multi-target-qubit unconventional geometric phase gate in a multi-cavity system. This multiqubit phase gate has a common control qubit but different target qubits distributed in different cavities, which can be achieved using a single-step operation. The gate operation time is independent of the number of qubits and only two levels for each qubit are needed. This multiqubit gate is generic, e.g., by performing single-qubit operations, it can be converted into two types of significant multi-target-qubit phase gates useful in QIP. The proposal is quite general, which can be used to accomplish the same task for a general type of qubits such as atoms, NV centers, quantum dots, and superconducting qubits.


Retrotransposon-derived promoter of Mammalian Aebp2.
Variable DNA methylation in promoter regions has been implicated in altering transcriptional regulation. The current study analyzed the evolutionary origin and DNA methylation pattern of one of the promoters of Aebp2. According to the results, the first promoter of Aebp2 has been derived from retrotransposons independently in the primate and rodent lineages. DNA methylation analyses revealed that this promoter is unmethylated in sperm, methylated in mature oocytes, and partially methylated at embryonic day 10.5 (78.3%) and 14.5 (58.3%). This promoter also shows variable levels of DNA methylation among adult organs, ranging from the highest in spleen (~80%) to the lowest in tail (~50%). The results from the F1 hybrid of interspecific crossing further indicated that both alleles are equally methylated without any allele bias, also supported by its biallelic expression. Therefore, the partial methylation observed among somatic tissues is an outcome of the genome-wide resetting of DNA methylation during the implantation stage, but not of the inherited allelic methylation pattern preset during gametogenesis. Taken together, mammalian Aebp2 has adopted retrotransposons as its promoter, which displays partial DNA methylation pattern of allelic- or non-allelic origin during the different stages of development.


Minimotifs dysfunction is pervasive in neurodegenerative disorders.
Minimotifs are modular contiguous peptide sequences in proteins that are important for posttranslational modifications, binding to other molecules, and trafficking to specific subcellular compartments. Some molecular functions of proteins in cellular pathways can be predicted from minimotif consensus sequences identified through experimentation. While a role for minimotifs in regulating signal transduction and gene regulation during disease pathogenesis (such as infectious diseases and cancer) is established, the therapeutic use of minimotif mimetic drugs is limited. In this review, we discuss a general theme identifying a pervasive role of minimotifs in the pathomechanism of neurodegenerative diseases. Beyond their longstanding history in the genetics of familial neurodegeneration, minimotifs are also major players in neurotoxic protein aggregation, aberrant protein trafficking, and epigenetic regulation. Generalizing the importance of minimotifs in neurodegenerative diseases offers a new perspective for the future study of neurodegenerative mechanisms and the investigation of new therapeutics.


The interference of operant task performance by emotional distracters: an antagonistic relationship between the amygdala and frontoparietal cortices.
This fMRI study investigates neural activity associated with the interfering effects of emotional distracters. While in the scanner, participants made simple motor responses to target stimuli that were preceded and followed by positive, negative, or neutral images. Despite instructions to disregard the pictorial images, participants were slower to respond in the presence of positive or negative relative to neutral distracters, and significantly slower for negative relative to positive distracters. Enhanced activity in the amygdala and visual cortex was evident during trials that included positive and negative distracters. In contrast, increased activity in inferior frontal gyrus (BA 47) was only observed during trials that involved negative distracters. Connectivity analysis showed that activity in right amygdala correlated with activity in cingulate gyrus, posterior cingulate, middle temporal cortex, and was negatively correlated with activity in lateral superior frontal gyrus, middle frontal/orbital gyrus, and parietal cortex. The pattern of neural activity observed was interpreted within the framework of current cognitive models of attention. During a task demonstrating behavioural interference in the context of emotional distracters, increased activity in neural regions implicated in emotional processing (the amygdala) was associated with reduced activity in regions thought to be involved in exerting attentional control over task-relevant sensory representations (a frontoparietal network).


Melanoma: criteria for histological diagnosis and its reporting.
The diagnosis of malignant melanoma requires clinical recognition of suspect lesions, biopsy, and histologic examination. Histological features which serve to distinguish malignant melanoma from their benign counterparts can be found in both the epidermis and dermis. The intraepidermal component of a common acquired nevus usually consists of more or less uniform theques of melanocytes located at or near the tips of rete ridges. Most melanomas are characterized by less orderly intraepidermal growth with areas in which melanocytes lose their nesting characteristics and are distributed more diffusely, sometimes replacing the basal keratinocytes by confluent growth and sometimes by invading upwards either as single cells or small nests into the upper reaches of the epidermis. Nested melanocytes can be found along the basal layer in malignant melanoma, but these nests are usually quite variable in size and location with respect to the tips of the rete ridges, and they are often irregularly distributed along the breadth of the lesion. The dermal component of malignant melanoma usually shows little tendency towards maturation, unlike that of benign nevi. Mitotic figures are unusual to find in the dermal component of common acquired nevi. When they are present, the possibility of melanoma should be considered. Other cytological features can also be useful in the diagnosis of malignant melanoma, particularly when there is marked cytological atypia; however, in some lesions, the cytological changes are not so pronounced and correct diagnosis depends on evaluation of growth pattern. While distinguishing between melanoma and atypical moles can be difficult, problems also arise in distinguishing melanoma from other neoplastic processes. The most common differential diagnosis includes melanoma, paget's disease, and pagetoid Bowen's disease. Desmoplastic melanoma is frequently difficult to distinguish from spindle cell squamous cell carcinoma and atypical fibroxanthoma. Histochemical and immunocytochemical stains are useful in resolving these problems. The pathology report of a melanoma should include the diagnosis, the maximum thickness of the tumor, the adequacy of the surgical margins (if the lesion has been excised), the presence or absence of ulceration, tumor regression, angiolymphatic invasion, and satellitosis. The inclusion of patients in treatment protocols may require additional information such as the host response of tumor-infiltrating lymphocytes, mitotic index, and Clark's level of invasion.


Health policy for persons with intellectual disability: experiences from Israel.
Intellectual disability (ID) is a life-long disability characterized by impaired cognitive and adaptive skills. Over the past few decades, a shift has occurred in the conceptualization and treatment of people with ID and research in health policy and health-care delivery has become increasingly global with a notable disparity between the developed and developing world. This review presents a literature overview of global health policy for ID with the intent to focus specifically on the policy and treatment within Israel. The methodology involved sites visits to care centers, discussions with stakeholders in health policy, and a literature review. We believe that Israel is in a unique position between a developed and developing culture. In particular, the distinct problems faced by the Arab and Bedouin community in terms of ID must be formally accounted for in Israel's future policies. Research from the developing world would be instructive to this end. The global approach in this presentation led to certain policy recommendations that take into account the uniqueness of Israel's position from a social, economic, religious, and demographic perspective. It is the hope that this paper will lead to an increased awareness of the challenges faced by persons with ID and their providers in all sectors of Israeli society and that the necessary policy recommendations will ultimately be adopted.


The broad spectrum revisited: evidence from plant remains.
The beginning of agriculture is one of the most important developments in human history, with enormous consequences that paved the way for settled life and complex society. Much of the research on the origins of agriculture over the last 40 years has been guided by Flannery's [Flannery, K. V. (1969) in The Domestication and Exploitation of Plants and Animals, eds. Ucko, P. J. & Dimbleby, G. W. (Duckworth, London), pp. 73-100] "broad spectrum revolution" (BSR) hypothesis, which posits that the transition to farming in southwest Asia entailed a period during which foragers broadened their resource base to encompass a wide array of foods that were previously ignored in an attempt to overcome food shortages. Although these resources undoubtedly included plants, nearly all BSR hypothesis-inspired research has focused on animals because of a dearth of Upper Paleolithic archaeobotanical assemblages. Now, however, a collection of >90,000 plant remains, recently recovered from the Stone Age site Ohalo II (23,000 B.P.), Israel, offers insights into the plant foods of the late Upper Paleolithic. The staple foods of this assemblage were wild grasses, pushing back the dietary shift to grains some 10,000 years earlier than previously recognized. Besides the cereals (wild wheat and barley), small-grained grasses made up a large component of the assemblage, indicating that the BSR in the Levant was even broader than originally conceived, encompassing what would have been low-ranked plant foods. Over the next 15,000 years small-grained grasses were gradually replaced by the cereals and ultimately disappeared from the Levantine diet.


Considerations for the design of antibody drug conjugates (ADCs) for clinical development: lessons learned.
Antibody-drug conjugates (ADCs) have emerged as a novel therapeutic strategy that has successfully reached patient treatment in different clinical scenarios. ADCs are formed by an antibody against a specific tumor-associated antigen (TAA), a cytotoxic payload, and a chemical linker that binds both. To this regard, most efforts have been focused on target identification, antibody design and linker optimization, but other relevant aspects for clinical development have not received the necessary attention. In this article using data from approved ADCs, we evaluated all characteristics of these agents, including payload physicochemical properties, in vitro potency, drug antibody ratio (DAR), exposure-response relationships, and clinical development strategies. We suggest that compounds with best options for clinical development include those with optimal payload physicochemical properties and cleavable linkers that would lead to a bystander effect. These modalities can facilitate the development of ADCs in indications with low expression of the TAA. Early clinical development strategies including changes in the schedule of administration with more frequent doses are also discussed in the context of an efficient strategy. In conclusion, we highlight relevant aspects that are needed for the optimal development of ADCs in cancer, proposing options for improvement.


Evolution of anti-HER2 therapies for cancer treatment.
The development of HER2-directed monoclonal antibodies and tyrosine kinase inhibitors have provided benefits to cancer patients, as well as produced many insights into the biology of the ErbB receptor family. Current therapies based on ErbB family members have resulted in improved overall survival with associated improvements in quality of life for the cancer patients that respond to treatment. Compared to monotherapy using either two antibodies to block the HER2 receptor blockade or combinatorial approaches with HER2 antibodies and standard therapies has provided additional benefits. Despite the therapeutic success of existing HER2 therapies, personalising treatment and overcoming resistance to these therapies remains a significant challenge. The heterogeneous intra-tumoural HER2 expression and lack of fully predictive and prognostic biomarkers remain significant barriers to improving the use of HER2 antibodies. Imaging modalities using radiolabelled pertuzumab and trastuzumab allow quantitative assessment of intra-tumoural HER2 expression, HER2 antibody saturation and the success of different drug delivery systems to be assessed. Molecular imaging with HER2 antibodies has the potential to be a non-invasive, predictive and prognostic technique capable of influencing therapeutic decisions, predicting response and failure of treatments as well as providing insights into receptor recycling and signalling. Similarly, conjugating HER2 antibodies with novel toxic payloads or combining HER2 antibodies with cellular immunotherapy provide exciting new opportunities for the management of tumours overexpressing HER2. Future research will lead to higher therapeutic responses, lower toxicities and providing insight into the mechanisms of resistance to HER2-targeted treatments.


Geometric characterization of cell membrane of mouse oocytes for ICSI.
Intracytoplasmic sperm injection (ICSI) is a broadly utilized assisted reproductive technology. A number of technologies for this procedure have evolved lately, such as the most commonly utilized piezo-assisted ICSI technique (P-ICSI). An important problem with this technique, however, is that it requires a small amount of mercury to stabilize the tip of the penetration micropipette. A completely different and mercury-free injection technology, called the rotationally oscillating drill (Ros-Drill) (RD-ICSI), was recently developed. It uses microprocessor-controlled rotational oscillations of a spiked micropipette after the pipette deforms the membrane to a certain tension level. Inappropriate selection of this initiation instant typically results in cell damage, which ultimately leads to unsuccessful ICSI. During earlier manual clinical tests of Ros-Drill, the technicians' expertise determined this instant in an ad hoc fashion. In this paper, we introduce a computer-vision-based tool to mechanize this process with the objective of maintaining the repeatability and introducing potential automation. Computer images are used for monitoring the membrane deformations and curvature variations as the basis for decision making. The main contribution of this paper is in the specifics of the computer logic to perform the monitoring. These new tools are expected to provide a practicable means for automating the Ros-Drill-assisted ICSI operation.


Dynamic tracking in interventional MRI using wavelet-encoded gradient-echo sequences.
This work describes a newly developed magnetic resonance imaging (MRI) data-acquisition strategy which replaces the standard Fourier phase-encoding with the spatially localized coefficients of wavelet-encoding and offers a new technique for image guidance when combined with a dynamic tracking algorithm. By using this new technique, only a specific fraction of the entire raw data set needs to be updated and reconstructed to visualize the movement of an interventional device during an MR guided procedure. The combination of wavelet-encoding and a dynamic tracking algorithm was implemented in two-dimensional and three-dimensional gradient-echo sequences on a 0.2-T open C-arm-shaped MR system (Siemens, Erlangen Germany) and tested in phantom and in vitro experiments. When applying the wavelet-encoding direction parallel to the movement of a straight interventional device, only those spatially localized wavelet-coefficients mainly affected by the interventional device are updated. This led to potential increases of the image frame rate by a factor of up to seven.


Susceptibility of clinical isolates to expanded-spectrum beta-lactams alone and in the presence of beta-lactamase inhibitors.
Tazobactam and BRL 42715 are relatively new penems which inhibit a wide range of plasmid- as well as chromosomally mediated bacterial beta-lactamases that include Richmond and Sykes type I, II, III, IV and V beta-lactamases, staphylococcal penicillins and extended-spectrum beta-lactamases. However, clavulanic acid, which is a potent inhibitor of class III beta-lactamases, is one of the first discovered compounds. We used a total of 645 recent clinical isolates, consisting of 305 Enterobacteriaceae, 180 gram-positive cocci and 160 other gram-negative bacteria to evaluate the ability of beta-lactamase inhibitors for potentiation of piperacillin, ticarcillin and amoxycillin. Minimum inhibitory concentrations for all the 42 strains of methicillin-susceptible Staphylococcus aureus were reduced 4- to 16-fold in the presence of beta-lactamase inhibitors. They were also highly effective in inhibiting the beta-lactamase of a wide variety of gram-negative bacteria, thereby changing their MIC values for amoxycillin, ticarcillin and piperacillin from a 'resistant' to a 'susceptible' range. Commonly resistant bacteria like Klebsiella, Enterobacter, Serratia, Acinetobacter and Pseudomonas were rendered susceptible to piperacillin and ticarcillin in the presence of clavulanic acid, tazobactam and BRL 42715. Of the commercially available formulations for clinical use, piperacillin/tazobactam (Tazocin) was found to be more inhibitory towards both gram-positive and gram-negative bacteria.


An X-band compact rectangular waveguide TE10-circular waveguide TE01 mode converter.
This paper proposed an X-band compact efficient rectangular waveguide TE10-circular waveguide TE01 mode converter and conducted its structure design, theoretical analysis, numerical simulation, and experimental research. This mode converter is composed of a rectangular waveguide TE10-TE20 mode converter and a rectangular waveguide TE20-circular waveguide TE01 mode converter. In the design of the rectangular waveguide TE20-circular waveguide TE01 mode converter, a rectangular waveguide step is used to counteract the microwave reflection due to the discontinuity of the rectangular-circular waveguide connection, and two choke slots are involved to suppress the TE21 mode in the circular waveguide by cutting off the axial component of its surface current on the waveguide wall, so as to improve the TE01 mode conversion efficiency. The simulation results show that the reflection coefficient of the mode converter is less than 5% and the TE01 mode conversion efficiency is about 98.4% at the operation frequency of 9.3 GHz. The bandwidth with a transmission coefficient greater than 98% is about 200 MHz. The back-to-back experimental system is demonstrated, and the experimental results show that the measured TE01 mode conversion efficiency is about 98.2%, which is consistent with the simulation result.


Food-addiction scale measurement in 2 cohorts of middle-aged and older women.
Excess weight is a major threat to public health. An addiction-like tendency toward certain foods may contribute to overeating. We aimed to describe the prevalence and associated characteristics in relation to a food-addiction scale in middle-aged and older women. We examined the prevalence and associated characteristics of a food-addiction scale measure in a cross-sectional analysis of 134,175 women participating in 2 ongoing prospective cohort studies of US nurses. Overall, 7839 (5.8%) of the women surveyed met the criteria for food addiction measured by using the modified Yale Food Addiction Scale. The prevalence of food addiction was 8.4% in the younger cohort of women aged 45-64 y and 2.7% in the older cohort of women aged 62-88 y. In the multivariate model, body mass index (BMI; in kg/m²) ≥ 35.0 (compared with 18.5-22.9) was associated with food addiction, a prevalence ratio (PR) of 15.83 (95% CI: 12.58, 19.91) in the younger cohort of women, and a PR of 18.41 (95% CI: 11.63, 29.14) in the older cohort of women. Several other demographic characteristics and other factors were associated with the food-addiction measure in both cohorts of women. To our knowledge, for the first time in a large, US-based population of women, we documented the prevalence of food addiction by using a novel measurement scale in middle-aged and older women. The results may provide insight into the strong association between behavioral attributes of food consumption and the development of obesity.


A comprehensive assessment of hurdle and zero-inflated models for single cell RNA-sequencing analysis.
Single cell RNA-sequencing (scRNA-seq) technology has significantly advanced the understanding of transcriptomic signatures. Although various statistical models have been used to describe the distribution of gene expression across cells, a comprehensive assessment of the different models is missing. Moreover, the growing number of features associated with scRNA-seq datasets creates new challenges for analytical accuracy and computing speed. Here, we developed a Python-based package (TensorZINB) to solve the zero-inflated negative binomial (ZINB) model using the TensorFlow deep learning framework. We used a sequential initialization method to solve the numerical stability issues associated with hurdle and zero-inflated models. A recursive feature selection protocol was used to optimize feature selections for data processing and downstream differentially expressed gene (DEG) analysis. We proposed a class of hybrid models combining nested models to further improve the model's performance. Additionally, we developed a new method to convert a continuous distribution to its equivalent discrete form, so that statistical models can be fairly compared. Finally, we showed that the proposed TensorFlow algorithm (TensorZINB) was numerically stable and that its computing speed and performance were superior to those of existing ZINB solvers. Moreover, we implemented seven hurdle and zero-inflated statistical models in Python and systematically assessed their performance using a real scRNA-seq dataset. We demonstrated that the ZINB model achieved the lowest Akaike information criterion compared with other models tested. Taken together, TensorZINB was accurate, efficient and scalable for the implementation of ZINB and for large-scale scRNA-seq data analysis with DEG identification.


Driving digital health transformation in hospitals: a formative qualitative evaluation of the English Global Digital Exemplar programme.
There is currently a strong drive internationally towards creating digitally advanced healthcare systems through coordinated efforts at a national level. The English Global Digital Exemplar (GDE) programme is a large-scale national health information technology change programme aiming to promote digitally-enabled transformation in secondary healthcare provider organisations by supporting relatively digitally mature provider organisations to become international centres of excellence. To qualitatively evaluate the impact of the GDE programme in promoting digital transformation in provider organisations that took part in the programme. We conducted a series of in-depth case studies in 12 purposively selected provider organisations and a further 24 wider case studies of the remaining organisations participating in the GDE programme. Data collected included 628 interviews, non-participant observations of 190 meetings and workshops and analysis of 9 documents. We used thematic analysis aided by NVivo software and drew on sociotechnical theory to analyse the data. We found the GDE programme accelerated digital transformation within participating provider organisations. This acceleration was triggered by: (1) dedicated funding and the associated requirement for matched internal funding, which in turn helped to prioritise digital transformation locally; (2) governance requirements put in place by the programme that helped strengthen existing local governance and project management structures and supported the emergence of a cadre of clinical health informatics leaders locally; and (3) reputational benefits associated with being recognised as a centre of digital excellence, which facilitated organisational buy-in for digital transformation and increased negotiating power with vendors. The GDE programme has been successful in accelerating digital transformation in participating provider organisations. Large-scale digital transformation programmes in healthcare can stimulate local progress through protected funding, putting in place governance structures and leveraging reputational benefits for participating provider organisations, around a coherent vision of transformation.


Characterizing environmental geographic inequalities using an integrated exposure assessment.
At a regional or continental scale, the characterization of environmental health inequities (EHI) expresses the idea that populations are not equal in the face of pollution. It implies an analysis be conducted in order to identify and manage the areas at risk of overexposure where an increasing risk to human health is suspected. The development of methods is a prerequisite for implementing public health activities aimed at protecting populations. This paper presents the methodological framework developed by INERIS (French National Institute for Industrial Environment and Risks) to identify a common framework for a structured and operationalized assessment of human exposure. An integrated exposure assessment approach has been developed to integrate the multiplicity of exposure pathways from various sources, through a series of models enabling the final exposure of a population to be defined. Measured data from environmental networks reflecting the actual contamination of the environment are used to gauge the population's exposure. Sophisticated methods of spatial analysis are applied to include additional information and take benefit of spatial and inter-variable correlation to improve data representativeness and characterize the associated uncertainty. Integrated approaches bring together all the information available for assessing the source-to-human-dose continuum using a Geographic Information System, multimedia exposure and toxicokinetic model. One of the objectives of the integrated approach was to demonstrate the feasibility of building complex realistic exposure scenarios satisfying the needs of stakeholders and the accuracy of the modelling predictions at a fine spatial-temporal resolution. A case study is presented to provide a specific application of the proposed framework and how the results could be used to identify an overexposed population. This framework could be used for many purposes, such as mapping EHI, identifying vulnerable populations and providing determinants of exposure to manage and plan remedial actions and to assess the spatial relationships between health and the environment to identify factors that influence the variability of disease patterns.


Coexistence of a ganglioglioma and Rasmussen's encephalitis.
A small number of recent reports have documented coexisting cerebral pathologic entities in patients with Rasmussen's encephalitis. We report the case of a 4-year-old boy who presented with refractory seizures and was found to have both a ganglioglioma and Rasmussen's encephalitis of the same hemisphere. The patient ultimately underwent a functional hemispherectomy with excellent seizure control. We also review the clinical and pathologic hallmarks of both gangliogliomas and Rasmussen's encephalitis. We hope that the addition of this patient to the small but growing literature on dual pathology in Rasmussen's encephalitis may help shed some light on the etiology of this mysterious disease.


Revascularization of tandem occlusions in acute ischemic stroke: review of the literature and illustrative case.
OBJECTIVE Tandem occlusions continue to represent a major challenge in patients with acute ischemic stroke (AIS). The anterograde approach with proximal to distal revascularization as well as the retrograde approach with distal to proximal revascularization have been reported without clear consensus or standard guidelines. METHODS The authors performed a comprehensive search of the PubMed database for studies including patients with carotid occlusions and tandem distal occlusions treated with endovascular therapy. They reviewed the type of approach employed for endovascular intervention and clinical outcomes reported with emphasis on the revascularization technique. They also present an illustrative case of AIS and concurrent proximal cervical carotid occlusion and distal middle cerebral artery occlusion from their own experience in order to outline the management dilemma for similar cases. RESULTS A total of 22 studies were identified, with a total of 790 patients with tandem occlusions in AIS. Eleven studies used the anterograde approach, 3 studies used the retrograde approach, 4 studies used both, and in 4 studies the approach was not specified. In the studies that reported Thrombolysis in Cerebral Infarction (TICI) grades, an average of 79% of patients with tandem occlusions were reported to have an outcome of TICI 2b or better. One study found good clinical outcome in 52.5% of the thrombectomy-first group versus 33.3% in the stent-first group, as measured by the modified Rankin Scale (mRS). No study evaluated the difference in time to reperfusion for the anterograde and retrograde approach and its association with clinical outcome. The patient in the illustrative case had AIS and tandem occlusion of the internal carotid and middle cerebral arteries and underwent distal revascularization using a Solitaire stent retrieval device followed by angioplasty and stent treatment of the proximal cervical carotid occlusion. The revascularization was graded as TICI 2b; the postintervention National Institutes of Health Stroke Scale (NIHSS) score was 17, and the discharge NIHSS score was 7. The admitting, postoperative, and 30-day mRS scores were 5, 1, and 1, respectively. CONCLUSIONS In stroke patients with tandem occlusions, distal to proximal revascularization represents a reasonable treatment approach and may offer the advantage of decreased time to reperfusion, which is associated with better functional outcome. Further studies are warranted to determine the best techniques in endovascular therapy to use in this subset of patients in order to improve clinical outcome.


Noninvasive assessment of preclinical atherosclerosis.
Initially considered as a semipermeable barrier separating lumen from vessel wall, the endothelium is now recognised as a complex endocrine organ responsible for a variety of physiological processes vital for vascular homeostasis. These include the regulation of vascular tone, luminal diameter, and blood flow; hemostasis and thrombolysis; platelet and leucocyte vessel-wall interactions; the regulation of vascular permeability; and tissue growth and remodelling. The endothelium modulates arterial stiffness, which precedes overt atherosclerosis and is an independent predictor of cardiovascular events. Unsurprisingly, dysfunction of the endothelium may be considered as an early and potentially reversible step in the process of atherogenesis and numerous methods have been developed to assess endothelial status and large artery stiffness. Methodology includes flow-mediated dilatation of the brachial artery, assessment of coronary flow reserve, carotid intima/media thickness, pulse wave analysis, pulse wave velocity, and plethysmography. This review outlines the various modalities, indications, and limitations of available methods to assess arterial dysfunction and vascular risk.


Screening of the antibacterial effects of a variety of essential oils on microorganisms responsible for respiratory infections.
The aim of this study was to examine the cytotoxicity and the antibacterial effects of a variety of essential oils on major respiratory tract pathogens. The cytotoxicity of 13 essential oils was evaluated on Vero cells. The antibacterial activity was evaluated by the Kirby Bauer paper method, minimum inhibitory and bactericidal concentration against Streptococcus pyogenes, agalactiae, pneumoniae and Klebsiella pneumoniae, Haemophilus influenzae, Staphylococcus aureus and Stenotrophomonas maltophilia isolated from clinical specimens. The antibiotic sensitivity of these isolates was examined. Some oils showed inhibition of bacterial growth against most of the organisms examined. Cinnamon and thyme showed the strongest action followed by clove. The results reported in this paper indicate that thyme can be considered as a potential antimicrobial agent for the treatment of some respiratory tract infections in man.


Curative chemotherapy for acute myeloid leukemia: the development of high-dose ara-C from the laboratory to bedside.
In the bench to bedside development of drugs to treat patients with cancer, the common guide to dose and schedule selection is toxicity to normal organs patterned after the preclinical profile of the drug. An understanding of the cellular pharmacology of the drug and specifically the cellular targets linked to the drug's effect is of substantial value in assisting the clinical investigator in selecting the proper dose and schedule of drug administration. The clinical development of ara-C for the treatment of acute myeloid leukemia (AML) provides a useful paradigm for the study of this process. An understanding of the cellular pharmacology, cytokinetics and pharmacokinetics of ara-C in leukemic mice showed substantial schedule-dependency. Exposure to high doses for a short duration (C x t) resulted in a palliative therapeutic outcome. In marked contrast, exposure to lower doses for a protracted period (c x T) was curative. Clinical use of ara-C in patients with AML patterned after the murine experience, c x T approach, has been of limited benefit in terms of long-term disease-free survival. Studies with human leukemia blasts from patients have shown that for the majority of patients, the initial rate-limiting step is membrane transport, the characteristics of which are substantially affected by extracellular drug concentration (dose). This pharmacologic impediment is eliminated with the blood levels attained during the infusion of gram doses (1-3 gm/m2) of the drug (high-dose ara-C, HiDaC) for shorter periods of time, a C x t approach. Clinical confirmation of these pharmacologic observations is evident in the therapeutic efficacy of HiDaC in patients with relapsed or SDaC-refractory acute leukemia. This is further emphasized by the significantly improved leukemia-free survival of patients with AML treated with HiDaC intensification during remission compared to those patients treated with milligram doses typical of SDaC protocols. Thus, the identification and monitoring of important parameters of drug action in tumors during the course of a clinical trial can be of substantial assistance in optimizing drug dose and schedule so as to attain the best therapeutic index.


Alginate bead fabrication and encapsulation of living cells under centrifugally induced artificial gravity conditions.
This study presents a novel method for the direct, centrifugally induced fabrication of small, Ca2+-hardened alginate beads at polymer-tube micronozzles. The bead diameter can arbitrarily be adjusted between 180-800 microm by the nozzle geometry and spinning frequencies between 5-28 Hz. The size distribution of the main peak features a CV of 7-16%, only. Up to 600 beads per second and channel are issued from the micronozzle through an air gap towards the curing agent contained in a standard lab tube ('Eppi'). Several tubes can be mounted on a 'flying bucket' rotor where they align horizontally under rotation and return to a vertical position as soon as the rotor is at rest. The centrifugally induced, ultra-high artificial gravity conditions (up to 180 g) even allow the micro-encapsulation of alginate solutions displaying viscosities up to 50 Pa s, i.e. approximately 50,000 times the viscosity of water! With this low cost technology for microencapsulation, HN25 and PC12 cells have successfully been encapsulated while maintaining vitality.


[Acute respiratory tract infections and acute coronary syndromes].
Epidemiological research indicates a correlation between respiratory-tract infections and acute cardiovascular events. Chronic infections have been linked to the development of atherosclerosis. As a result of chronic infections a prolonged and elevated inflammatory activity arises. Inflammation and the associated vessel-wall damage play an important role in the pathophysiology of atherosclerosis. Acute infections have been linked to a transient increased risk of unstable angina pectoris and an acute myocardial infarct. The consequence of acute infections is a systemic inflammatory response which results in changes in the atherosclerotic plaque, thrombotic activation and a prothrombotic condition. The inflammatory response and prothrombotic condition reinforce each other. This can result in coagulation on ruptured atherosclerotic plaques and erosions in the vessel wall, which can give rise to the sudden constriction or blockage of coronary arteries.


Molecular evidence for the involvement of alpha crystallin in the colouration/crosslinking of crystallins in age-related nuclear cataract.
The proteins of the lens which become insoluble, crosslinked and coloured as a result of the onset of human nuclear cataract have been studied using a combination of enzymatic digestion and HPLC/mass spectrometry (MS). The objective was to determine if such an approach could provide information on the identities of the polypeptide components involved in the colouration and crosslinking and to discover whether any crystallins predominate in this characteristic post-translational modification process. Initially, coloured high molecular weight peptides were isolated from a tryptic/chymotryptic digest of the 6 M guanidine hydrochloride-insoluble lens protein fraction. These tryptic/chymotryptic peptides were then incubated with pronase and the small peptides released, purified by gel filtration. All but one of the peptides analysed by HPLC/MS/MS were found to contain proline. Peptides derived from alpha-crystallin were found to comprise the great majority of the peptides characterised. No gamma-crystallin peptides were observed. Both alpha A-crystallin and alpha B-crystallin were represented. Further, all but one of these peptides were derived from the N-terminal region of the alpha-crystallin subunits: a region recently implicated in the chaperone activity of alpha-crystallin. This finding suggests that the putative N-terminal domain of alpha-crystallin may be involved at the molecular level in the process of crosslinking and colouration which is known to be characteristic of age-related nuclear cataract. It is, therefore, conceivable that an early stage of these cataractous modifications may involve alpha-crystallin acting as a molecular chaperone.


Destruction of the cell membrane and inhibition of cell phosphatidic acid biosynthesis in Staphylococcus aureus: an explanation for the antibacterial mechanism of morusin.
Morusin is a prenylated flavonoid found in mulberry that shows antimicrobial activity against foodborne pathogens. The MIC values of morusin toward S. aureus ATCC 6538 and S. aureus ATCC 25923 were both 14.9 μmol L-1. This study further investigated the antimicrobial mechanism of morusin in inhibiting the growth of Staphylococcus aureus ATCC 6538. Scanning electron microscopy and transmission electron microscopy revealed that morusin disrupted the integrity of the bacterial cell membrane. Morusin may also affect the phospholipid-repair system of bacteria, which repairs membrane structures. To test this hypothesis, quantitative real-time PCR was used to examine the effect of morusin treatment of S. aureus on the regulation of genes associated with the cell phosphatidic acid biosynthesis pathway. Gas chromatography-mass spectrometry was used to investigate the fatty acid components, which are used to synthesize bacterial phosphatidic acids. In summary, the results revealed that morusin showed a potent antibacterial effect by disrupting the cell membrane architecture and inhibiting the phosphatidic acid biosynthesis pathway of S. aureus.


Translating Fatigue to Human Performance.
Despite flourishing interest in the topic of fatigue-as indicated by the many presentations on fatigue at the 2015 Annual Meeting of the American College of Sports Medicine-surprisingly little is known about its effect on human performance. There are two main reasons for this dilemma: 1) the inability of current terminology to accommodate the scope of the conditions ascribed to fatigue, and 2) a paucity of validated experimental models. In contrast to current practice, a case is made for a unified definition of fatigue to facilitate its management in health and disease. On the basis of the classic two-domain concept of Mosso, fatigue is defined as a disabling symptom in which physical and cognitive function is limited by interactions between performance fatigability and perceived fatigability. As a symptom, fatigue can only be measured by self-report, quantified as either a trait characteristic or a state variable. One consequence of such a definition is that the word fatigue should not be preceded by an adjective (e.g., central, mental, muscle, peripheral, and supraspinal) to suggest the locus of the changes responsible for an observed level of fatigue. Rather, mechanistic studies should be performed with validated experimental models to identify the changes responsible for the reported fatigue. As indicated by three examples (walking endurance in old adults, time trials by endurance athletes, and fatigue in persons with multiple sclerosis) discussed in the review, however, it has proven challenging to develop valid experimental models of fatigue. The proposed framework provides a foundation to address the many gaps in knowledge of how laboratory measures of fatigue and fatigability affect real-world performance.


[The pulsatile LH fluctuation (spiking) dependent on the circulating prolactin. Studies during physiological (puerperium), functional pathological and TRH induced hyperprolactinemia].
The magnitude and frequency of episodic LH-fluctuations have been observed to change during the different phases of the menstrual cycle. A hypothalamic control center appears to be responsible for these variations. Disturbances of the hypothalamus often make themselves known through a lack of LH-episodes. Ahypothalamic derangement in women with functional amenorrhoea can result in a disregulation of gonadotropins as well as prolactin, thereby leading to hyperprolactinemia. One finds an inverse relationship between high prolactin secretion and cessation of or decreased pulsatile LH-secretion (spiking). LH-spiking was tested in physiological post partum, functional pathological and TRH-induced hyperprolactinemias. No LH-episodes were observed post partum after the end of HCG clearance although prolactin had returned to normal levels at 12 days p.p. The mode of LH-secretion in a group of functionally amenorrhoic patients was changed by a TRH-induced prolactin increase: the previously observed LH-spikes in these women could no longer be seen. Normal cycling women, however, were not affected. In patients with hyperprolactinemic anovulatory syndromes, prolactin suppressed LH-fluctuations reappeared after administration of 2-Bromo-alpha-ergocryptin. The inhibitory influence of hyperprolactinemia on the function of the gonadostat will be discussed. High plasma prolactin levels influence the cyclic and tonic hypothalamic function. Furthermore, prolactin appears to have a peripheral inhibitory influence on ovarian gonadotropin stimulation. Post partum anovulation and amenorrhoea can be caused by an antigonadotropic and antigonadic effect of prolactin.


Impact of body mass index on seminal oxidative stress.
Male obesity has been linked with a reduction in sperm concentration and motility, an increase in sperm DNA damage and changes in reproductive hormones. Recent large observational studies have linked male obesity with a reduced chance of becoming a father. One of the potential underlying pathological mechanisms behind diminished reproductive performance in obese men is sperm oxidative stress. The primary aim of this study was to determine if sperm oxidative stress was more common in obese/overweight men. A total of 81 men had their body mass index (BMI) correlated with seminal reactive oxygen species (ROS) production (Nitro Blue Tetrazolium assay), sperm DNA damage (TUNEL), markers of semen inflammation (CD45, seminal plasma PMN elastase and neopterin concentration) and routine sperm parameters, together with reproductive hormones. The principal finding from this study was that oxidative stress did increase with an increase in BMI, primarily due to an increase in seminal macrophage activation. However, the magnitude of this increase was small and only of minor clinical significance as there was no associated decline in sperm DNA integrity or sperm motility with increasing ROS production. Increased BMI was also found to be significantly linked with a fall in sperm concentration and serum testosterone, and an increase in serum oestradiol.


Systemic interferon-alpha (IFN-alpha) treatment leads to Stat3 inactivation in melanoma precursor lesions.
In the setting of familial melanoma, the presence of atypical nevi, which are the precursors of melanoma, is associated with a nearly 100% risk of developing primary melanoma by age 70. In patients with sporadic melanoma, it is estimated that 40-60% of melanomas develop in contiguous association with atypical nevi. Currently, the only way to prevent atypical nevi from progressing to melanoma is to monitor and excise them as soon as they exhibit changes in their clinical features. Activation of the transcription factor, Stat3, has been linked to abnormal cell growth and transformation as well as to interferon alpha (IFN-alpha)-mediated growth suppression in vitro. To determine whether IFN-alpha, used for adjuvant therapy of high-risk, resected melanoma, induces changes in Stat3 in atypical nevi, patients with a clinical history of melanoma who have multiple atypical nevi were treated for 3 months with low-dose IFN-alpha. Thereupon, the new technology of microscopic spectral imaging and biochemical assays such as electrophoretic mobility shift assays (EMSAs) and immunoblot analysis were used for the study of atypical nevi, obtained before and after IFN-alpha treatment. The results of the investigations provided evidence that, as a result of systemic IFN-alpha treatment, Stat1 and Stat3, which are constitutively activated in melanoma precursor lesions, lose their ability to bind DNA, and as shown in the case of Stat3, become dephosphorylated. Unlike primary and metastatic melanomas, melanoma precursor lesions cannot be established as cell cultures. Thus, the only way to explore pathways and treatment regimens that might help prevent progression to melanoma is within the context of a melanoma precursor lesion study conducted prospectively. The findings presented here suggest that down-regulation of the transcription factors Stat1 and Stat3 by systemic IFN-alpha treatment may represent a potential pathway to prevent the activation of gene(s) whose expression may be required for atypical nevus cells to progress to melanoma.